The FDA’s recent rejection of midomafetamine (MDMA), along with mental-health therapy, for the treatment of post-traumatic stress disorder (PTSD) came as no surprise. Lykos Therapeutics, formerly MAPS, has come under attack for missing safety data, therapist misconduct and a culture of psychedelic evangelism. The journal Psychopharmacology retracted three papers about MDMA-assisted psychotherapy. The FDA’s recommendation that Lykos repeat the studies is unavoidable, but the FDA should engage more effectively as well.
The decision prolongs — probably for a decade — the availability of much-needed treatments. It is harmful, for all the veterans and millions suffering from PTSD and thousands more on the edge of suicide, desperate to escape the agonies of their lives. The FDA and other governmental agencies have failed to step up when mental health challenges abound.
Studies show that only half of the approved treatments for PTSD and related problems benefit the patients. Many cannot tolerate the side effects of recommended medications and refuse to take them. That leaves half of these patients left to struggle, and some considering or committing suicide.
The FDA, after reviewing all available data in 2016, granted Breakthrough Therapy Designation to MAPS in 2017 and approved the designs of two phase 3 trials for MDMA that started in 2018. In granting breakthrough designation, the FDA had reviewed the data from the Phase 1 and 2 studies. The agency had been alerted to the unparalleled challenges for implementing the novel therapy and the concerns over designing and conducting the studies in the early phases. The FDA and other governmental agencies had six years to tackle the problems and guide better procedures for developing treatments and therapies.
The criticisms of the advisory committee and rejection by the FDA mimic the usual scripts of the experts and bureaucrats that staff these procedures. The agency pointed out the absence of effective placebos and weak methodologies as deficiencies in conducting the research. But designing double-blind studies or figuring out placebos for MDMA and other psychedelics is unrealistic.
Psychedelics are powerful medicines that work in unique ways, and subjects can guess whether the right drug has been given to them. The mental health field and the FDA can take a page out of cancer research that applies comparative efficacy design. The subject receives treatment that is already established to be effective, instead of placebo, and experts assess the effectiveness of the experimental treatment.
The FDA criticized the studies for failures to document harm, expectations about treatment, and euphoric effects. MDMA, like other potent medicines, have powerful effects as well as expose patients to “harm” or worsening symptoms. Any drug that can have a substantive effect — relieving the most serious problems — has potential for harm. The expectation to be helped by a drug or therapy is basic to good clinical care. To deny or ignore such an expectation may be unethical.
Expressions of humanity are part and parcel of a good therapy session and understandably enhance the placebo effect, including euphoria that can give a lasting benefit. It is also not surprising that some subjects experienced worse suicidal ideation and felt depressed. The FDA has put black box warnings on many antidepressants for the increased risk of suicidal thoughts, feelings and behavior. Some patients often feel worse even in the first days after starting talk therapy.
No matter what the FDA decides about MDMA, people are going to use psychedelics to treat their mental illnesses. The FDA and other governmental agencies have not faced that reality, as thousands veterans have gone offshore seeking treatment. Our government is not protecting these men and women from harm by delaying implementation of the therapies.
As a psychiatrist and retired brigadier general (U.S. Army), I arranged meetings three years ago with senior officials at Health and Human Services. I hoped to alert them to the challenges in developing and deploying MDMA and other psychedelic medicines. The novel psychedelic modalities have come on the scene at an inflection point when mental health services are fragmented and fall short of meeting the needs of many. I urged them to convene the drug developers, experts in policy and decision makers to jumpstart needed shifts for improving mental health care.
That has yet to happen and is very disappointing, but not surprising. Psychedelic treatments disrupt the current modes of mental health care. The VA and other governmental systems are not prepared to deploy the novel therapy with MDMA. The failure to seize leadership painfully protracts deployment and denies the availability of vital treatments.
Knowing that life-threatening circumstances and the tragedies of day-to-day mental health conditions are growing, the health care profession is obligated to diligently and thoughtfully pursue promising efforts. I advised the HHS leadership that it needed to proactively engage the advocates, drug developers and its own staff to effectively deploy the treatments.
Governmental agencies all too often act like “fast followers” and avoid leading change. They have not grasped the details and nuances of the disruptive impact of psychedelics, how to innovate better policies and practices, and how to build an infrastructure for patient-centered, individualized care. The approval and deployment of psychedelic treatments and therapies should shake up mental health care and force big shifts in care delivery.
What we know about psychedelics justifies the FDA and companion agencies to exercise initiative and implement bold plans to save men and women at the end of their rope. The challenge for introducing novel therapies requires attacking fundamental problems in mental health research and practice with a full-court coordinated campaign.
Stephen N. Xenakis, M.D., is a psychiatrist and retired Army brigadier general.
